N-(trans-4-isopropyl cyclohexylcarbonyl)-D-phenylalanine, generally known as nateglinide, is an antidiabetic drug used as a hypoglycemic agent in patients with type II diabetes. Nateglinide has the following structural formula:

The synthesis of nateglinide is previously described in U.S. Pat. No. 4,816,484, and employs the activated N-hydroxy succinimide ester of trans-4-isopropyl cyclohexanecarboxylic acid as an intermediate for condensation with a D-phenyl alanine alkyl ester. The alkyl ester of nateglinide shown below, where R is an alkyl group, is obtained after reaction between the above referred to activated ester of trans-4-isopropyl cyclohexanecarboxylic acid and a D-phenyl alanine alkyl ester

It is taught by U.S. Pat. No. 4,816,484 that the above alkyl group acts as a protecting group, limiting the amount of undesirable side reactions. The overall process described in U.S. Pat. No. 4,816,484 for the preparation of nateglinide can be represented as follows:

However, it has now been found that by following the process as described in U.S. Pat. No. 4,816,484, the nateglinide ester is found to be present in an undesirable amount in the final nateglinide product. Also, crystallization of nateglinide from aqueous methanol results in undesirable further esterification.
Chinese Journal of Medicinal Chemistry, Vol. 12, page no: 94, describes the synthesis of trans-4-isopropylcyclohexane carboxylic acid through reduction of 4-isopropylbenzoic acid, which on reaction with N-hydroxyphthalimide in presence of N′N′-dicyclohexylcarbodiimide gives the activated N-hydroxyphthalimide ester. This is subjected to acylation reaction with D-phenylalanine ethyl ester, and subsequent hydrolysis gives nateglinide.
Journal of Medicinal Chemistry, 1989, Vol. 32, No. 7, page no: 1437, describes the reaction of trans-4-isopropylcyclohexane carboxylic acid with dicyclohexylcarbodiimide and N-hydroxysuccinimide to form the activated N-hydroxysuccinimide ester. This is then reacted with D-phenylalanine methyl ester, and subsequent hydrolysis gives nateglinide.
PCT Application WO2004/018408 describes a method for the synthesis of nateglinide which includes reacting trans-4-isopropylcyclohexane carboxylic acid with an alkyl chloroformate of the formula ClCO2R, where R is an alkyl group, to form a trans-4-isopropylcyclohexane mixed acid anhydride. The mixed acid anhydride is then reacted with an aqueous alkali salt solution of D-phenylalanine to yield a reaction mixture including nateglinide.
U.S. Pat. No. 5,463,116 discloses stable crystals of nateglinide. The nateglinide is first produced according to the method described in Example 3 of Japanese patent application laid open no. 63-54321 (an equivalent of U.S. Pat. No. 4,816,484).
EP1334963A discloses a method for producing nateglinide crystals from a reaction mixture containing nateglinide. The nateglinide is obtained by reacting trans-4-isopropylcyclohexane carboxylic acid chloride with D-phenylalanine in a mixed solvent of a ketone and water in the presence of an alkali, followed by neutralisation with an acid. Specific adjustment of the temperature of the mixture and the concentration of ketone solvent results in precipitation of nateglinide crystals. The ketone solvent(s) in the reaction is usually essential to proceed the reaction. However, a large quantity of acetone in the reaction causes high proportion of by-product.
PCT Application WO 2004/005240 describes a process for the preparation of nateglinide by reacting trans-4-isopropyl cyclohexane carboxylic acid chloride with a suitable salt of D-phenyl alanine in presence of an effective amount of an organic amide.
D-phenylalanine used as the starting material in the processes of EP1334963A and WO 2004/005240 is not protected by an alkyl group, so reaction of the unprotected carboxylic acid group leads to undesirable side products.
There exists a need for improved processes for the preparation of nateglinide.